Glaucoma is one of the leading causes of blindness worldwide. Elevated intraocular pressure (IOP) is the primary risk factor for optic nerve damage in glaucoma. Many studies conducted on human subjects and animal models have shown that marijuana and its active components cannabinoids lower IOP. This project is focused on understanding the mechanisms by which cannabinoids, potential therapeutic agents for glaucoma, lower intraocular pressure (IOP). In the previous funding period, we have established that CB1 and CB2 cannabinoid receptors are expressed on the trabecular meshwork (TM) cells, and cannabinoid agonists enhance aqueous humor outflow through both CB1 and CB2 receptors. For the competitive renewal application of this project, we hypothesize that non-CB1/CB2 cannabinoid derivatives may cause an enhancement of aqueous humor outflow through a novel, non-CB1/CB2 cannabinoid receptor, and the novel cannabinoid receptor may mediates the IOP-lowering effects of the non-CB1/CB2 cannabinoid agonists through metalloprotease (MMP)-mediated mechanisms. Two specific aims are designed to test the above three hypotheses. Specific Aim 1: To study the effects of non-CB1/CB2 cannabinoid agonists, and the role of GPR55, a novel, non- CB1/CB2 cannabinoid receptor on aqueous humor outflow. Specific Aim 2: To study the mechanisms of actions for the aqueous humor outflow-enhancing effects of non-CB1/CB2 cannabinoid agonists. Completing this project should provide mechanistic insight regarding cannabinoid-induced enhancement of aqueous humor outflow facility. These studies should also contribute to our understanding of the homeostasis of aqueous humor outflow and may lead to the development of better therapeutic agents for lowering IOP.